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1.
Cardiovasc Drugs Ther ; 29(2): 129-35, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25712416

ABSTRACT

BACKGROUND: Pretreatment with high-dose statins given before percutaneous coronary intervention (PCI) has been shown to have beneficial effects, in particular by reducing peri-procedural myocardial infarction. The mechanism of these lipid-independent beneficial statin effects is unclear. Circulating endothelial progenitor cells (EPCs) have an important role in the process of vascular repair, by promoting re-endothelization following injury. We hypothesized that statins can limit the extent of endothelial injury induced by PCI and promote re-endothelization by a positive effect on EPCs. We, therefore, aimed to examine the effect of high-dose statins given prior to PCI on EPCs profile. METHODS: Included were patients, either statin naïve or treated chronically with low-dose statins, with stable or unstable angina who underwent PCI. Patients were randomized to receive either high-dose atorvastatin (80 mg the day before PCI and 40 mg 2-4 h before PCI) or low- dose statin. EPCs profile was examined before PCI and 24 h after it. Circulating EPCs levels were assessed by flow cytometry as the proportion of peripheral mononuclear cells co-expressing VEGFR-2+ CD133+ and VEGFR-2+ CD34+. The capacity of the cells to form colony forming units (CFUs) was quantified after 7 days of culture. RESULTS: Twenty three patients (mean age 61.4 ± 7.4 years, 87.0% men) were included in the study, of which 12 received high-dose atorvastatin prior to PCI. The mean number of EPC-CFUs before PCI was higher in patients treated with high-dose atorvastatin vs. low-dose statins (165.8 ± 58.8 vs. 111.7 ± 38.2 CFUs/plate, respectively, p < 0.001). However, 24 h after the PCI, the number of EPC-CFUs was similar (188.0 ± 85.3 vs. 192.9 ± 66.5 CFUs/plate in patients treated with high-dose atorvastatin vs. low- dose statins, respectively, p = 0.15). There were no statistical significant differences in FACS analyses between the 2 groups. CONCLUSIONS: The current study showed higher EPC- CFUs levels in patients treated with high-dose atorvastatin before PCI and a lower increment in EPC-CFUs after PCI. These findings could account for the beneficial effects of statins given prior to PCI, yet further investigation is required.


Subject(s)
Atorvastatin/administration & dosage , Atorvastatin/pharmacology , Endothelial Progenitor Cells/drug effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Myocardial Infarction/prevention & control , Percutaneous Coronary Intervention/adverse effects , Atorvastatin/therapeutic use , Cell Count , Dose-Response Relationship, Drug , Female , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Male , Middle Aged , Stem Cells/drug effects
2.
Mol Cell Biochem ; 345(1-2): 153-60, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20730620

ABSTRACT

Activation of either the A(1) adenosine receptor (A(1)R) or the A(3) adenosine receptor (A(3)R), by their specific agonists CCPA and Cl-IB-MECA, respectively, protects cardiac cells in culture against ischemic injury. Yet the full protective mechanism remains unclear. In this study, we therefore examined the involvement of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases (ERK) phosphorylation in this protective intracellular signaling mechanism. Furthermore, we investigated whether p38 MAPK phosphorylation occurs upstream or downstream from the opening of mitochondrial ATP-sensitive potassium (K(ATP)) channels. The role of p38 MAPK activation in the intracellular signaling process was studied in cultured cardiomyocytes subjected to hypoxia, that were pretreated with CCPA or Cl-IB-MECA or diazoxide (a mitochondrial K(ATP) channel opener) with and without SB203580 (a specific inhibitor of phosphorylated p38 MAPK). Cardiomyocytes were also pretreated with anisomycin (p38 MAPK activator) with and without 5-hydroxy decanoic acid (5HD) (a mitochondrial K(ATP) channel blocker). SB203580 together with the CCPA, Cl-IB-MECA or diazoxide abrogated the protection against hypoxia as shown by the level of ATP, lactate dehydrogenase (LDH) release, and propidium iodide (PI) staining. Anisomycin protected the cardiomyocytes against ischemic injury and this protection was abrogated by SB203580 but not by 5HD. Conclusions Activation of A(1)R or A(3)R by CCPA or Cl-IB-MECA, respectively, protects cardiomyocytes from hypoxia via phosphorylation of p38 MAPK, which is located downstream from the mitochondrial K(ATP) channel opening. Elucidating the signaling pathway by which adenosine receptor agonists protect cardiomyocytes from hypoxic damage, will facilitate the development of anti ischemic drugs.


Subject(s)
Adenosine A1 Receptor Agonists/pharmacology , Adenosine A3 Receptor Agonists/pharmacology , Hypoxia/prevention & control , Myocytes, Cardiac/pathology , p38 Mitogen-Activated Protein Kinases/physiology , Adenosine/analogs & derivatives , Animals , Extracellular Signal-Regulated MAP Kinases/metabolism , Heart , Hypoxia/diet therapy , Myocytes, Cardiac/drug effects , Phosphorylation , Potassium Channels , Protective Agents/pharmacology , Rats
3.
Eur J Vasc Endovasc Surg ; 40(3): 381-8, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20226697

ABSTRACT

OBJECTIVES: It is a common clinical observation that collateral vessel development is impaired in diabetic patients with ischaemic vascular diseases. Consequently, alternative revascularisation strategies in diabetic patients are needed. This study presents the effect and mechanism of new peptide therapeutic angiogenesis in an ischaemic and diabetic mouse model. DESIGN: Streptozocin-injected mice that had undergone hind-limb ischaemia were treated with angiogenic peptides. Blood flow restoration was calculated by laser Doppler imager and corroborated by histological section. For the mechanism study, endothelial cells were exposed to hypoxia and high glucose concentrations to study the effect of the peptides on proliferation and anti-apoptosis. RESULTS: The peptides significantly restored blood perfusion 21 days after surgery in the diabetic mice (p < 0.01) by neo-vascularisation, corroborated by an increase in capillary density. In addition, the peptides induced the proliferation of hypoxic endothelial cells (p < 0.01) and protected the cells from apoptosis in high glucose cultures. CONCLUSIONS: This is the first approach for treatment of ischaemic vascular disease with peptides in a diabetic mouse model.


Subject(s)
Angiogenesis Inducing Agents/pharmacology , Capillaries/drug effects , Diabetes Mellitus, Experimental/drug therapy , Diabetic Angiopathies/drug therapy , Ischemia/drug therapy , Muscle, Skeletal/blood supply , Neovascularization, Physiologic/drug effects , Peptides/pharmacology , Animals , Apoptosis/drug effects , Blood Glucose/metabolism , Capillaries/pathology , Capillaries/physiopathology , Cell Hypoxia , Cell Proliferation/drug effects , Cells, Cultured , Collateral Circulation/drug effects , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Experimental/physiopathology , Diabetic Angiopathies/etiology , Diabetic Angiopathies/pathology , Diabetic Angiopathies/physiopathology , Disease Models, Animal , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Endothelial Cells/pathology , Female , Hindlimb , Humans , Ischemia/etiology , Ischemia/pathology , Ischemia/physiopathology , Laser-Doppler Flowmetry , Mice , Mice, Inbred C57BL , Regional Blood Flow/drug effects , Time Factors
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